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Factor V Leiden (FVL) and Prothrombin G20210A are the most common genetic thrombophilias known to increase the risk of initial venous thromboembolism (VTE). Although testing to detect these mutations has been available since 2003, and now widely available to clinicians, the value of screening for these disorders has yet to be determined. A systematic review published in the June 2009 issue of JAMA set out to investigate if the presence of either mutation predicts VTE recurrence in those with a history of VTE or a first occurrence in family members with either mutation. They also looked for evidence to suggest if genetic testing for FVL or Prothrombin G20210A improves patient outcomes.

The review included 46 articles evaluating either: 1) the rates of VTE recurrence among adults with FVL or Prothrombin G20210A mutations compared to those without, 2) the rates of initial VTE among family members of those with a history of VTE and 1 of the aforementioned mutations based on the presence or absence of a mutation in the family member, or 3) the rates of recurrence based on anticoagulation treatment in adults with FVL or Prothrombin G20210A compared to those without.

Recurrence rates in individuals with a history of VTE varied based on the type of mutation and whether the subjects were heterozygous or homozygous. (Table 1) Both heterozygosity and homozygosity for FVL increased the rate of recurrence when compared to those without FVL (OR 1.56 and 2.65 respectively). The risk of recurrence was not affected by the presence of FVL in those where the initial event was idiopathic. However 1 study did find an increased risk of recurrence for FVL when the initial events were provoked (OR 6.5). Recurrence was not affected by heterozygosity for Prothrombin G20210A or the presence of both mutations, and data was insufficient to assess differences in those homozygous for Prothrombin G20210A.

When evaluating the incidence of initial VTE events in family members of those with a history of VTE and either FVL or Prothrombin G20210A, the reviewers found that family members heterozygous for FVL had a higher occurrence of VTE as compared to those without the mutation (OR 3.49) as did family members homozygous for FVL (OR 18) and those heterozygous for both mutations (OR 6.7). (Table 2) Although data were limited, the authors did not find an increased rate of occurrence in family members heterozygous for Prothrombin G20210A compared to those without the mutation. Data was insufficient to evaluate the incidence of VTE in family members homozygous for Prothrombin G20210A.

Although genetic testing is often conducted to guide treatment decisions, the authors noted the lack of trials directly assessing such practice on outcomes. They reviewed 4 trials that included patients with and without FVL and Prothrombin G20210A mutations evaluating the benefit of anticoagulation treatment on VTE recurrence. One comparing low intensity warfarin to placebo demonstrated treatment with low intensity warfarin reduced the rate of recurrence by 75% (HR 0.25; 95% CI, 0.07-0.85) in those with either mutation. This benefit was not found to be significantly different from the 58% risk reduction in patients without either mutation (HR 0.42; 95% CI, 0.20-0.86)(p=0.51). The remaining 3 studies reported similar findings; treatment of those with FVL or Prothrombin G20210A mutations provides the same risk reduction as in those without either mutation.

The authors note several weaknesses of their review. They only included articles written in English. The inclusion of observational studies may have increased the potential for confounding. Many studies simply did not evaluate other risk factors for VTE and others failed to report patient-level data for the authors of the review to evaluate for potential confounders. In the trials evaluating risk to family members, the inclusion criteria was unclear in many cases and varied between trials. There was a concern of publication bias for those with double heterozygosity based on the potential for small studies to report large effects. The effect of increased surveillance of family members of those with a genetic disorder should also be noted. The wide CIs and small sample size of these family studies also make it more difficult to draw definitive conclusions in general.

Strengths of the review include: all studies evaluating VTE recurrence were prospective; the duration of initial anticoagulation treatment in most trials was at least 3 months, although some were not reported; follow-up after the index event was at least 2 years in the majority of trials (mean range: 6-99 months; not reported in 3); the authors assessed the individual quality of each article as well as the overall evidence for each mutation; heterogeneity and publication bias was evaluated and reported; and the authors sequentially removed each study from the calculation of the pooled estimate and reported any variations in the calculated odds ratio. Although the potential for confounding was a concern, individual trials using a multivariate model failed to identify specific confounders.

The authors concluded that although there is evidence to suggest an increased rate of recurrence in those with FVL and initial events in family members with FVL, the value of testing for this mutation remains uncertain. Moderate data suggests the risk of recurrence is not higher for those heterozygous for Prothrombin G20210A, however, data are lacking concerning homozygosity for Prothrombin G20210A and those heterozygous for both mutations. While there is strong evidence to support the benefit of treatment in those with either mutation, this benefit appears to be similar to those without either mutation. Varying results from individual trials suggests the occurrence of VTE is multifactorial, including non-genetic factors with varying risks. Further research is needed to determine the value of testing as it relates to treatment decisions and patient outcomes.

Table 2: Summary of event rates for first VTE in family members of those with either FVL or Prothrombin G20210A

Mutation studied

# of studies

# of events / total # with mutation

# of events / total # without mutation

Pooled OR (95% CI)

Level of Evidence

Family members heterozygous for FVL vs without

7

166/1156

46/940

3.49 (2.46-4.96)

Moderate

Family members homozygous for FVL vs without

6

17/48

41/850

18 (7.8-40)

High

Family members heterozygous for Prothrombin G20210A vs without

3

2/24

14/267

1.89 (0.35-10)

Insufficient

Family members heterozygous for both FVL and Prothrombin G20210A vs without

4

11/59

24/674

6.7 (2.9-16)

Low

NR= Not reported

*Amanda Hollingsworth and Mary Long are PharmD candidates at Auburn University Harrison School of Pharmacy (AUHSOP) in Auburn, AL. Lori B. Hornsby, PharmD, BCPS is Assistant Clinical Professor, Department of Pharmacy Practice at AUHSOP. Additionally, she is an Ambulatory Clinical Pharmacist at Columbus Regional Healthcare System in Columbus, GA.